The mechanism of T-helper cell depletion in HIV disease is poorly understood. Results from several in vitro studies have suggested that the interaction of the HIV envelope glycoprotein with the viral receptor, the CD4 glycoprotein, has an important role in T-helper cell loss. Such an interaction may be deleterious to infected cells, which express both proteins, as well as to uninfected cells that express CD4. It has been suggested, for example, that soluble envelope glycoprotein, gp120, shed from virus particles or infected cells, can sensitize cells for the activation of a cell death pathway or for their targeting by cytotoxic T cells. It is also possible that the multimeric envelope glycoprotein expressed on the surface of infected cells can block maturation of CD4+T- helper cells or can induce signals that result in the death of these cells through an apoptotic mechanism. We have developed a transgenic mouse system that will facilitate testing of some of these hypotheses. The human CD4 gene, under the regulation of the murine CD4 enhancer, has been introduced into mice in which the endogenous CD4 gene has been ablated. The human CD4 molecule is appropriately expressed only on the T-helper subset in these mice and developmental regulation of the transgene appears to be identical to that of the normal murine CD4 gene. In addition, the human CD4 molecule substitutes for murine CD4 and rescues T-helper cell development in the CD4-null mice. Animals in which murine CD4 is functionally replaced with human CD4 (hCD4 mice) will be used to determine whether in vivo administration of soluble or multimeric HIV envelope glycoprotein results in impaired T cell development and/or T-helper cell function. In addition, transgenic mice expressing gp120 or gp160 in T cells or in antigen presenting cells will be prepared and will be crossed to the hCD4 mice; this will allow us to determine if interaction of envelope glycoprotein and CD4 within T cells or through cell-cell interactions has a deleterious effect on T cell development and function. To test whether soluble gp120 can sensitize CD4+ T cells for destruction by cytotoxic T cells, mice expressing human MHC class II molecules on the surface of their T lymphocytes will be prepared and will be crossed to the hCD4 mice; the offspring will be injected with gp120 and evidence of T cell cytolysis will be sought. Finally, the interaction of the HIV Nef protein and human CD4 will be studied in this transgenic system. An intact Nef gene has been shown to be essential for the pathogenic effect of the simian immunodeficiency virus in rhesus monkeys. Nef expression has been shown to down-regulate surface expression of CD4 in cell lines and to impair T cell development in Nef transgenic mice. To test whether Nef affects human CD4-dependent development of T-helper cells, mice transgenic for both Nef and human CD4 will be prepared and analyzed.